1. Field of the Invention
Antibiotic A-23187 is a unique polyether antibiotic having the following structure ##STR1## The numbering system used herein for A-23187 is that proposed by M. O. Chaney, Noel D. Jones and Manuel Debono in J. Antibiotics 29 (4), 424-427 (1976).
In Westley's review on polyether antibiotics, he classifies ionophores by chemical structure [see J. W. Westley in "Advances in Applied Microbiology," Vol. 22, D. Perlman, Ed., Academic Press, New York, N.Y., 1977, pages 177-223]. Using Westley's classification, there are four types of ionophore antibiotics: (1) polyethers; (2) peptides; (3) cyclodepsipeptides; and (4) macrotetrolides. Within the polyether subclass, there are four subgroups: (1a) monovalent polyethers (e.g., monensin, nigericin); (1b) monovalent monoglycoside polyethers (e.g., dianemycin); (2a) divalent polyethers (e.g., lasalocid, lysocellin) and (2b) divalent pyrrole ethers (e.g., antibiotic A-23187). To date, antibiotic A-23187 is the only known member of this last group.
Ionophore A-23187 has proven to be a powerful and unique research tool to investigate Ca.sup.2+ -dependent control mechanisms in a large variety of cellular systems. Calcium (Ca.sup.2+) ion is widely recognized as an intracellular "second messenger" [H. Rasmussen and D. P. B. Goodman, Physiological Reviews 57 (3), 421-509 (1977)]. The mechanisms by which Ca.sup.2+ controls cellular excitation phenomena appear similar to, and linked to, control by cyclic nucleotides and prostaglandins.
Of approximately 100 known, naturally occurring ionophores, A-23187 is one of three which are able to transport divalent cations significantly. A-23187 is the only ionophore substantially selective for the transport of divalent over monovalent cations.
Despite this unique utility, A-23187 is not an ideal Ca.sup.2+ ionophore from a physiological viewpoint. It transports Mg.sup.2+ with a similar efficiency to Ca.sup.2+, and its discrimination for divalent over monovalent cations is not complete [D. R. Pfeiffer and H. A. Lardy, Biochemistry 15, 935 (1976)].
2. The Prior Art
Bromo derivatives of the polyether antibiotics lasalocid A (antibiotic X-537A; U.S. Pat. No. 3,873,715) and iso-lasalocid A (U.S. Pat. No. 3,944,573) are known. The complex structure of antibiotic A-23187, however, precludes any a priori prediction of the site(s) of halogenation.